Systemic hormonal signals which stimulate bone resorption are modulated in a site specific manner by local factors. Among the most important local regulators of skeletal homeostasis are physical stimuli. One proposed mechanism for the response of bone to loading is that local mechanical stimuli generate an electric field which can be sensed by bone tissue as osteoregulatory. Indeed, time varying electric fields have been used with success to prevent disuse osteoporosis in animals. Therefore, we have hypothesized that the formation of osteoclasts, the cell effectors of bone resorption, is modulated by the local electric field. In preliminary work, using a unique electromagnetic system capable of inducing uniform and quantifiable electric fields in vitro, we have shown that time varying electric fields attenuate the 1,25(OH)2D-driven formation of osteoclast-like cells from the murine marrow culture system. We propose to extend these observations, defining the characteristics of the local field responsible for attenuation of osteoclastogenesis, and investigating interactions of the field with hormone regulators of bone resorption. In this four year study a systematic series of in vitro experiments is proposed which involves applying electric fields during recruitment of osteoclasts from the murine marrow model system. 1,25(OH)2D-driven osteoclast formation will be assessed by counting of osteoclast-like cells and assay of TRAP content/well after an 8 day culture period. Cells plated in square well dishes will be placed within experimental electric fields induced by creating a time varying magnetic field within a solenoid coil. Sham exposed cells will be subjected to similar vibrational and thermal variations within a solenoid receiving a constant electric current, which induces a null magnetic field. We will examine which components of the electric field are responsible for inhibition of osteoclast formation, testing frequency and intensity characteristics as well as the number of hours per day required for maximal attenuation. The ability of electric fields (using the most efficacious field) to inhibit marrow cell colony proliferation supported by M-CSF, GM-CSF or IL-3 in semisolid media will then be examined to indicate at which point during recruitment the field modulates osteoclast formation. We will then examine the ability of these fields to attenuate the recruitment of osteoclasts by factors (besides 1,25(OH)2D) known to be important in osteoclast differentiation: M-CSF, GM-CSF and IL-6. Field effects to diminish secretion by the marrow culture of these factors will also be studied using standard bioassays to assess field treated media. These experiments should provide unique insights into the normal, site specific control of bone turnover. Further, by identifying those electric fields which modulate osteoclast formation, a novel therapeutic regimen for the local treatment of areas at high risk of involutional bone loss becomes possible.